APPLICANT'S ABSTRACT: Well-recognized inter-individual differences in the propensity to develop alcoholic liver disease (ALD) suggest that co-dependent variables are likely to influence susceptibility to alcohol-induced hepatotoxicity. Bacterial infections are not widely believed to alter susceptibility to ALD. However, the latter issue may merit reconsideration given emerging evidence which suggests that a) certain gram negative enteric pathogens can cause hepatitis in non-alcoholic subjects and b) gut-derived bacterial products (e.g., endotoxin) trigger the hepatic production of pro-inflammatory cytokines (including TNFalpha, IL-6 and IL-8) which have been incriminated in the pathogenesis of ALD. The purpose of this project is to explore the relationship between enteroinvasive gram negative bacteria and ALD by studying a group of Mexican alcoholic patients who are likely to have enteric infections. We hypothesize that infection with gram negative enteric pathogens potentiates the genesis of ALD by increasing hepatic cytokine production. To test this theory we will: 1) evaluate serum titers of anti-lipid A antibodies and endotoxin, enteroinvasive bacterial DNA in liver, and stool cultures to determine the prevalence of infection with gram negative enteroinvasive bacteria in Mexican and U.S. patients with ALD and with non-alcoholic liver disease; 2) grade the clinical and histological severity of liver disease in ALD patients and evaluate TNFalpha, IL-6 and IL-8 gene expression in these patients to determine if enteric infection is an independent predictor of liver disease severity and/or cytokine gene expression; 3) evaluate the types of alcoholic beverages consumed and the levels and pattern of alcohol consumption in patients with ALD to determine if the prevalence of enteroinvasive bacterial infection is higher in patients who have developed ALD with low levels of alcohol intake than in patients who develop it with high levels of consumption; and 4) search for enteroinvasive bacteria and endotoxin in pulque, a Mexican beer that is consumed in regions with a high-prevalence of ALD. These studies provide a unique opportunity to examine the importance of gut-derived products in the pathogenesis of ALD in humans and may suggest novel strategies to decrease alcohol-related morbidity.